This is Dr. Robert Warriner and this the second of a two part presentation on the role and value of hyperbaric oxygen treatment in diabetic and ischemic healing and limb salvage.

~3

Production of this PRESENT lecture was made possible by a generous grant from Sechrist. Leading the way in hyperbaric oxygen medicine.

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I am the Chief Medical Officer of Diversified Clinical Services in Jacksonville, Florida and I am the founding and emeritus medical director of the South East Texas Center for Wound Care and Hyperbaric Medicine at Cornell Regional Medical Center in suburban north Houston. I have no disclosures that affect the objectivity of this program.

~5

In this presentation, we will review the role of hypoxia in diabetic ulcer healing failure the clinical value of hyperbaric oxygen treatment in diabetic and ischemic limb salvage and we will look at a brief overview of the process of evaluating and selecting patients for hyperbaric oxygen treatment.

~6

This patient represents an all too frequent occurrence in our practice of complex wound management.

~7

At any time in the United States as many as 1 million diabetics are suffering from a lower extremity ulcer constituting 20% of all hospital admissions and contributing to 50-70% of lower extremity amputations. All of which is associated with an increase in both short and long term complications.

~8

Pecoraro and others have shown that 80-85% of diabetic lower extremity amputations are preceded by an ulcer and that 60% of these ulcers are infected. In addition malprofusion or ischemia plays a major role in diabetic ulcer healing failure and ultimately in diabetic limb loss.

~9

In fact there is a broad range of presentation of diabetic foot ulcers with respect to microbial imbalance and infection. All the way from those relatively uncomplicated minimally contaminated ulcer to those with present in a setting of limb and life threatening progressive necrotizing soft tissue infections.

~10

Not only is infection problematic but now profusion contributes a significant risk as well. In the spectrum of the typically clinical practice of diabetic foot ulcer care, patients can be seen with all degrees of malprofusion from mild to moderate, all the way again to severe ischemia and hypoxia, threatening immediate limb loss.

~11

Reiber has nicely summarized the causal chain of in the pathophysiology of diabetic limb loss and has emphasized the importance of faulty healing leading to gangrene and eventual limb loss. It is this area of faulty healing to which we will next turn our attention.

~12

Mostoe in an excellent review in the American Journal of Surgery in 2004 of the pathophysiology of chronic wound healing failure identified three critical aspects of chronic wounds. Some of which are minimal to direct intervention. He identified the cellular and systemic effects of aging as having an adverse outcome on chronic wound healing. The role of bacteria colonization or other intermittent or continuous stimulation of local inflammatory responses and finally the chronic ischemia, hypoxia and repeated ischemia-reperfusion injury with are often seen in this setting of constant local ischemia and are major contributors to ongoing wound healing failure.

~13

Looked at from a slightly different perspective as shown in this slide. Whether we are looking at pressure ulcers, ulcers due to venous insufficiency, or ulcers due to diabetes, there are commonalities in the pathophysiology. All of which relate to some degree of tissue ischemia, the possibility of cycles of ischemia-reperfusion and the presence of small vessel dysfunction which may be due to alterations and vasomotor responsiveness or impaired diffusion. The end result of these interactions is the activation of a vascular inflammatory pathologic state which supports progressive wound healing failure.

~14

This vascular inflammatory activation leads to abnormal patterns of cytokine and other inflammatory mediator release and persistence in the wound bed. Leukocyte extravasations and heighten leukocyte activity with subsequent protienase activation, red cell leakage with its contribution to reactive oxygen metabolites, increase trans-capillary permeability leading to local tissue edema, fibrinogen leakage, fibrin deposition and thrombin activation. The combination of all of these events leads to what is often a persistently ischemic, hypoxic and inflammatory rich environment.

~15

Within the [inaudible] of the chronic non-healing wound, a number of molecules are of particular interest, including growth factors such as platelet-derived growth factors, vascular endothelial growth factor, fibroblast growth factors, and epidermal growth factors. Inflammatory mediators such as Interleukin I, II and Interleukin 6, the matrix metalloproteinase, calmodulin carrier and nitric oxide. Nitric oxide is of particular importance as it occupies a central role in mediating normal wound healing. Reduced levels of nitric oxide have been shown to impair normal wound healing in a variety of circumstances.

~16

This figure illustrates the role of nitric oxide in the healthy wound on the left and the diabetic wound on the right. Not that on the left increased eNOS activation through the wound lead to increased nitric oxide levels which support vascular endothelial cell and smooth muscle migration, angiogenesis and a formation of a healthy bed of granulation tissue. Unfortunately in the diabetic wound, decreased levels of eNos lead to decreased nitric oxide levels in the wound bed, leading to impaired vascular and endothelial cell migration, impaired smooth muscle cell migration, impaired angiogenesis and delayed wound healing.

~17

Going back to Mustoeâs model for chronic wound healing failure, letâs now focus on the role of chronic ischemia, hypoxia, repeated ischemia-reperfusion injury and look at the potential value for the application of hyperbaric oxygen treatment to reverse this component of the wound healing failure.

~18

Pecoraro in 1991 identified hypoxia in diabetic foot wounds as a major prognostic indicator for diabetic ulcer healing failure. In fact Pecoraro identified that when the transcutaneous PO2 was less than 20mm of mercury there was a 39 fold increase risk of early ulcer healing failure in diabetes.

~19

This hypoxia may be the result of large vessel peripheral arterial occlusive disease resulting in chronic underlying ischemia and hypoxia.

~20

It may be the result of microcirculatory dysfunction which would exacerbate any macrovascular disease present. This microvascular dysfunction could be related to alterations and response to inflammatory stress, vasomotor dysfunction and capillary basement and membrane thickening with altered capillary permeability.

~21

And finally the impact of motor deformity and neuropathy producing areas of high pressure leading to intermittent recurrent ischemia-reperfusion injury cycles.

~22

Regardless of the factors contributing to malperfusion, the diabetic foot ulcer with associated hypoxia looks something like this cartoon representation. There is hypoxic necrotic wound center, surrounded by a zone of tissue injury of variable size based on the mechanism and extent of injury. That zone of injury is then surrounded by an area of malperfused hypoxic periwound tissue which is poorly configured to support ulcer wound healing.

~23

In fact the great the degree of local tissue hypoxia as evidenced in this graft with transcutaneous PO2 values decreasing from 40 mm of mercury which would be considered a minimum cut off to support normal wound healing down to 0 mm of mercury with increasing tissue hypoxia there is increased risk of wound healing failure. At some point tissue hypoxia is such that wound healing can no longer occur.

~24

In summary, regardless of the mechanism of local tissue hypoxia and malperfusion hypoxia is a major predictory of primary diabetic ulcer healing failure and a major target for intervention to prevent diabetic ulcer healing and limb salvage.

~25

A number of interventions are possible to correct this underlying malperfusion. They include vascular and surgical revascularization techniques to increase blood flow. Interventions to decrease local tissue edema, interventions to increase oxygen carrying capacity such as correction of chronic enema and possibly the addition of adjunctive hyperbaric oxygen therapy. Most of our interventions to correct hypoxia produce a partial resolution of periwound hypoxia, elevating PO2s to some level but frequently not raising those PO2 levels back to the normal range.

~26

Hyperbaric oxygenation on the other hand produces a state of supranormal tissue oxygen availability by transiently raising PO2 to levels much higher than can be achieved under physiologic conditions regardless of the state of local blood flow.

~27

Hyperbaric oxygen treatment is the use of 100% oxygen breathed at increased atmospheric pressure. It requires that the patient be enclosed in a pressure vessel, be subjected to an atmospheric pressure of at least 1.5 times sea level or ambient pressure and that the patient be breathing 100% oxygen. Typically hyperbaric oxygen treatment is administered in either of two environments. On the left is a multi-place hyperbaric chamber filled with air and compressed with air with patients receiving 100% oxygen by a tight fitting mask or a hood. On the right is a typical mono-place hyperbaric chamber in which the patient is compressed breathing 100% oxygen. The ambient oxygen environment eliminates the need for a hood or a mask for oxygen administration. Each of these environments has its advantages and disadvantages. The principle advantage of the multi-place chamber is that patient contact during treatment is possible and multiple patients can be treated at the same time. However these environments are much more complex, and more expensive, both to manufacture and to operate than the mono-place chamber shown on the right. The mono-place chamber accomplishes exact the same therapeutic environment and provides the same therapeutic benefits at a much lower cost and a lower operating complexity although the patient is isolated from direct contact by the care giver. The mono-place chamber offers one additional advantage. That is that it allows the specific tailoring of treatment pressure and treatment profile to the individual patient.

~28

Remember that hyperbaric oxygenation of wounds leads to increased tissue oxygen which can affect a number of critical aspects in wound healing including the potentiation of antibiotic function, direct effects on anaerobic bacteria and enhanced leukocyte mobility, phagocytosis and bacterial killing, increased collagen synthesis, alterations in the regulation of blood flow which favor the redistribution of flow to ischemia tissue, inflammatory cell activation and deactivation based upon the particular circumstances of hyperbaric oxygen exposure. Regulation of gene expression through nitric oxide mediated and other pathways. Regulation of cell proliferation, regulation and support of angiogenesis and stimulation of bone marrow mesenchymal and hematopoietic stem cell mobilization and activation. Many of these effects persist after the completion of hyperbaric oxygen treatment particularly those involving cell signaling and altering cell and tissue responsiveness.

~29

Now letâs turn our attention to the clinical evidence in support of the role of hyperbaric oxygen treatment in neuropathic diabetic chronic foot ulceration.

~30

A number of randomized controlled clinical trials have been performed assessing the effectiveness of hyperbaric oxygen treatment in ischemia and diabetic ulcer chronic non-healing wounds. The most important of these studies and the one which subsequently led to the development of a Medicare coverage policy for hyperbaric oxygen treatment in diabetic ulcer healing failure was the study by Faglia, published in Diabetes Care in 1996.

~31

Faglia is a vascular surgeon from Milan, Italy. He is published extensively in the areas of endovascular and surgical revasculation interventions in diabetic limb salvage. In addition he is published the single most important prospective control randomized clinical trial of hyperbaric oxygen treatment in diabetic limb salvage. We will now look at that study in a little more detail to help us develop an approach to the application of hyperbaric oxygen treatment in diabetic limb salvage.

~32

The study involves 68 patients originally 35 in each group, but 2 in the control or non-HBO group were lost to follow-up. All patients underwent an aggressive regime for optimization of metabolic control with near normalization of hemoglobin A1C values in all patients during the course of care. All patients with ABI less than 0.9 or transcutaneous PO2 values less 50 mm of mercury received arteriography and if possible intervention by angioplasty or bypass grafting was performed without regard to whether or not they were to receive hyperbaric oxygen. The hyperbaric oxygen treatment protocol was a standard multi-place treatment protocol as would be typically used in routine clinical practice. Limb salvage was the primary end point and was considered when plantar support was preserved and the ulcer healed despite minor amputations, including toe amputations, ray resections or transmetarsal amputations. Major amputation decisions were carried out by a consultant surgeon who was unaware of the patientsâ treatment in the conventional hyperbaric arm of the study. Note that patients admitted to this study were Wagner Grade 3 or greater for diabetic foot ulcer presentations.

~33

The results of the Faglia study are as follows. In the HBO treatment group of 35 patients, three or 8.6% required a major amputation, 2 of which were below the knee, 1 of which was an above the knee amputation. In the conventional care group which differed only in that hyperbaric oxygen treatment was not provided 11 of 33 patients or 33% had major amputations which included 7 below the knee and 4 above the knee amputations and this difference in amputation rate was statistically significant. It was also noted that transcutaneous PO2 values increased significantly in the HBO treated subjects compared to those in the conventional group regardless of whether or not revascularization could be accomplished. Negative prognostic determinants were low ABI values which could not be correct by Wagner grades. It was this study which subsequently was used by the Center for Medicare and Medicaid Services to develop its current diabetic foot ulcer coverage guideline for hyperbaric oxygen treatment.

~34

Subsequent to the Faglia study, Fife et al in 2002 published a series of 1144 diabetic patients retrospectively analyzed all of which received adjunctive hyperbaric oxygen treatment. The first publication of this data addressed the minimum transcutaneous PO2 value required during hyperbaric oxygen treatment to predict a favorable outcome. The conclusion that retrospective review was that in chamber or during hyperbaric oxygen treatment, transcutaneous PO2 values in excess of 200 mm of mercury, were required to predict a favorable outcome with respect to hyperbaric oxygen treatment.

~35

The second publication from this retrospective series of patients appeared in Wound Repair Regeneration in 2007 and addressed factors influencing the outcome of diabetic foot ulcer patients who received hyperbaric oxygen treatment. It is important to note that the presence of renal failure, persistence of cigarette smoking, and non-revascularizable peripheral arterial disease of the lower extremities were major negative prognostic factors in this review.

~36

This is a subset of data from the 1144 diabetic foot ulcer patients receiving hyperbaric oxygen treatment in the 2 Repair and Regeneration Publications. This is the sample group that excludes those patients with renal failure or who had other adjunctive therapies. It is significant to note that 77% of those with Wagner Grade 3, 64% with Wagner Grade 4 and 29.7% of those with Wagner Grade 5 were able to have salvage of bipedal amputation. It is also important to note that in those patients with demonstrated hypoxia by transcutaneous PO2 who were Wagner Grade 2, 83% of those demonstrated ulcer healing and this is a significant improvement over the healing percentages of Wagner Grade 1 and 2 patients in clinical trials for other technologies such as regranics, appligraph, and dermagraph. Noting also that these patients were hypoxic at the time of presentation. It is particularly interesting to note hyperbaric oxygen treatment is typically applied in this setting of persistent infection underlying osteomyllitis and uncorrectable malperfusion. These inclusion criteria for the application of hyperbaric oxygen treatment have been exclusion criteria for patients in other studies in advanced technology for diabetic foot ulcer healing.

~37

Hyperbaric oxygen treatment has been subject to independent evidence based reviews. One of the most significant being that completed by the Cochrane Review Group and published in 2004.

~38

To quote the summary from the Cochrane Review, âPeople with foot ulcers due to diabetes, HBOT significantly reduced the risk of major amputation and may improve the chance of healing in 1 year. The application of HBOT to these patients may be justified where HBOT facilities are available. However, economical evaluation should be undertaken.â

~39

In fact, several cost effectiveness analyses of hyperbaric oxygen therapy in diabetic limb salvage have been completed and published. This review by Guo published in the International Journal of Technology Assessment in Health in 2003 revealed the following based upon a cost effectiveness model developed from the design and outcome of the five randomized control clinical trials of hyperbaric oxygen treatment in diabetic ulceration.

~40

In a 1000 patient theoretical cohort model, 155 cases of major lower extremity amputation were averted by the application of hyperbaric oxygen treatment and adding significantly to quality of life years obtained in this patient setting. While hyperbaric oxygen treatment was expensive in the setting of short term survival with each increase in survival year, the cost of hyperbaric oxygen treatment dropped significantly. Clearly hyperbaric oxygen treatment is most cost effective based upon a long term perspective and when patients are properly selected. This is an ideal place for the application of in chamber transcutaneous PO2 measure to predict more accurately those patients likely to respond to hyperbaric oxygen treatment and intervention.

~41

Healing with hyperbaric oxygen treatment in diabetic foot ulcer care is also durable. Cianci and Hunt in Wound Repair and Regeneration in 1997 published a large series of patients which demonstrated 94% maintenance of an intact limb and heal wound at an average duration of 55 months post closure. Kalani et al in 2002 published a series which demonstrated 76% healing rate with maintenance of intact skin at 3 years compared to 48% healing in the control group at 3 years. Also a 12% amputation rate in the HBO group versus a 33% ultimately amputation rate in the control group at 3 years.

~42

In 2002 the Center for Medicare and Medicaid Services published a specific coverage memorandum for hyperbaric oxygen for diabetic foot ulcers requiring that the patient have type 1 or type 2 diabetes, a lower extremity wound attributable to diabetes, of Wagner Grade 3 or greater. That they have failed standard wound care for 30 days, treatments must be validated by re-evaluation at 30 day intervals and must show measurable signs of improvement at each interval for hyperbaric oxygen treatment to be continued.

~43

The value of hyperbaric oxygen treatment in acute peripheral arterial insufficiency ulcer exam and limb salvage in critical limb ischemia in the absence of diabetes is a more complicated study. No direct evidence for cost effectiveness has been studied because the overwhelming majority included in the various clinical trials have had diabetes which is a confounding fact. However preventing a below the knee amputation by salvaging a ray resection or a transmetasal amputation or preventing progression from below the knee to above the knee amputation would certainly be a satisfactory outcome in this group of patients. Also wounds of a purely ischemic nature treated with hyperbaric oxygen treatment as have diabetic ulcers excellent long term durability.

~44

Finally recent guidelines published by the Wound Healing Society in 2006 for diabetic ulcer care and arterial insufficiency ulcer care have ascribe level of evidence values for adjunctive hyperbaric oxygen treatment. The diabetic ulcer guideline for hyperbaric oxygen was given a level 1A evidence for application in diabetic foot ulcer healing and the purely ischemic ulcer category of HBO was given a level of IIB evidence.

~45

This final slide summarizes the process by which patients are typically assessed and managed with adjunctive hyperbaric oxygen treatment. Patients present with a wound whose etiology is determined to be amenable to favorable impact by hyperbaric oxygen treatment. When possible a transcutaneous PO2 study is performed to define the extent and persistence of local tissue hypoxia. While pre- hyperbaric oxygen treatment transcutaneous PO2 values are not required under any reimbursement model for hyperbaric oxygen treatment, the base line transcutaneous PO2 value defining the significance of the degree of resting hypoxia and can be an important prognostic indicator. Certainly transcutaneous PO2 values less than 50 in a diabetic, less than 40 in a non-diabetic should drive one to consideration of adjunctive hyperbaric oxygen treatment. At that point, a medical assessment with respect to potential risk factors for hyperbaric oxygen treatment should be undertaken. The only absolute contraindication to hyperbaric oxygen treatment would include the concomadated administration of neomycin or ambeoteraon? Both potent pulmonary oxygen toxicity desensitivity desensitizers, the presence of an untreated pneumothorax, or the presence of other medical instability such as the patient cannot be managed effectively. Once absolute contraindications have been ruled out and relative contraindications have been optimized, the patient is then ready to begin adjunctive hyperbaric oxygen treatment. The treatment profile is set based upon recommendation from the medical literature and the Undersea and Hyperbaric Medical Society Oxygen Therapy committee report. Typically the treatments are administered for elective chronic wound indications at 2.0 ATA or 2.4 ATA with 90 minutes of 100% oxygen breathing being the norm. In those cases in which severe ischemia or progressive infection are being treated, higher treatment pressures 2.8 to a maximum pressure of 3.0 atmospheres absolute may be considered. In all cases, air breaks must be provided at treatment pressures greater than 2.8 ATA to reduce the risk of central nervous system acute oxygen toxicity. Certainly in all diabetic lower extremity wounds and in shape? Or transcutaneous PO2 measurements should be made during the first or second adjunctive hyperbaric oxygen treatment and target that value to predict likely benefit of therapy is 200 mm of mercury. Protocols do exist to assess those patients who fail to reach the 200 mm of mercury on initial treatment but are beyond the scope of this discussion. Throughout treatment the patient is continually reassessed looking for objective indications of improvement and local host response to and resolution of infection and improvement in the amount and quality of granulation tissue development and contraction and re-epilitialization. Typically patients are reassessed at 10-30 day intervals depending on the nature of the underlying etiology of wound healing failure. When hyperbaric oxygen treatment is provided in a manner as outlined above, treatment is both substantially beneficial and cost effective and represents important adjunct to diabetic and ischemic wound and limb salvage.

~46

Production of this PRESENT lecture was made possible by a generous grant from Sechrist. Leading the way in hyperbaric oxygen medicine.

~47

Thank you for your time and your attention to this presentation on the mechanisms of hyperbaric oxygen treatment and its effective application in diabetic and ischemic limb salvage.

At the completion of this presentation the student should understand the role of hyperbaric oxygenation in support of diabetic ulcer healing and limb salvage.

Goals and Objectives

After participating in this activity, the viewer should be better able to:
1. Understand how the pathophysiology of diabetic ulcer healing failure is at least in part reversed by hyperbaric oxygen treatment and the benefits to healing provided in this setting.2. Know the rationale for the use of HBO in hypoxic wounds and the clinical evidence supporting its use.

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